Composition for treating chronic venous insufficiencies using an extract of red vine leaves

ABSTRACT

The invention relates to a dietary supplement consisting of an aqueous extract of red vine leaves and an acceptable carrier which prevents and reduces the discomfort relating to mild-to-moderate chronic venous insufficiency of the legs.

RELATED APPLICATION DATA

[0001] This application is a continuation of U.S. application Ser. No.10/262,703, filed Oct. 2, 2002, which is a divisional of U.S.application Ser. No. 09/691,003, filed Oct. 18, 2000, both of whichclaim, as does the present application, priority benefit to U.S.Provisional Application serial No. 60/160,518 filed Oct. 20, 1999, thedisclosures of all of which are incorporated by reference in theirentirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to a dietary supplement, and moreparticularly, to a dietary supplement for preventing or alleviating thediscomfort associated with mild-to-moderate chronic venous insufficiencyof the lower extremities.

BACKGROUND OF THE INVENTION

[0003] Presently, there are millions of people around the world whosuffer from mild-to-moderate chronic venous insufficiency of the legs.This common condition is characterised by an inadequacy of the venouscirculation to return blood from the legs to the heart. The lack ofadequate venous return results in venous stasis and an increasedpressure within the venous circulation, promoting the development ofoedema and tissular water retention.

[0004] Chronic venous insufficiency (CVI) is a functional disordercaused by persistent inadequacy of the venous return and ischaracterised clinically by oedema, skin changes and subjectivecomplaints such as tired, heavy legs, pain or tingling sensations, whichare typically amplified by standing upright and by high ambienttemperatures. This dysfunction may be a source of major distress with asignificant negative impact on the patient's overall well-being andquality of life. Early stages (grade I) are characterised by coronalphlebectasia paraplantaris, subfascial congestion and oedema; grade IICVI is associated with low-grade skin changes, eczema andlipodermatosclerosis. If untreated, grades I and II often progress to anadvanced stage characterised by recurrent venous leg ulcers (grade III).The distress caused by the symptoms, even when relatively mildinitially, and the risk of later complications call for appropriatesupportive and preventive measures to be initiated in the early stagesof CVI.

[0005] Although some patients, even at early stages, might requiresurgery (sclerotherapy and variceal surgery), the use of compressionstockings with or without additional physiotherapy is the most commontreatment approach. The effect of compression is merely mechanical, i.e.this approach does not affect or correct the related biologicaldysfunction (capillary fragility in particular). Furthermore, thetreatment with compression stockings often lacks compliance because ofcosmetic concerns and the overall inconvenience of the compressivestockings, in the summer in particular. Therefore there is an urgentneed for alternative approaches that are effective, well-tolerated andmore convenient.

BRIEF DESCRIPTION OF THE INVENTION

[0006] Surprisingly, it has been found that an aqueous extract of redvine leaves can be used for the preparation of a dietary supplement forthe prevention and treatment of the discomfort associated withmild-to-moderate chronic venous insufficiency of the lower extremities.

[0007] The present invention therefore relates to a method forpreventing and/or alleviating the discomfort associated withmild-to-moderate chronic venous insufficiency of the lower extremities,which method comprises administering a dietary supplement containing anaqueous extract of red vine leaves.

[0008] Another aspect of the present invention is a dietary supplementcomposition which comprises an active principle being capable ofpreventing and/or treating the discomfort associated withmild-to-moderate chronic venous insufficiency of the lower extremitiesand an pharmaceutically, cosmetically or dietetically acceptablecarrier, the improvement wherein is that said active principleessentially consists of an aqueous extract of red vine leaves.

[0009] The dietary supplement composition of the present inventionpreferably consists of herbal ingredients derived by an aqueousextraction from red vine leaves (folia vitis viniferae; Extractum Vitisviniferae e folium spissum et siccum) and an acceptable carrier. Thisextract contains flavon(ol)-glycosides, -glucuronides and flavonoids,with quercetin-3-O-β-D-glucuronide and isoquercitrin(quercetin-3-O-β-glucofuranoside) as its main active ingredients. Therange of their pharmacological actions has not yet been fullyelucidated, but in-vitro studies indicate that they have antioxidant andanti-inflammatory properties and that they inhibit platelet aggregationand hyaluronidase and reduce oedema, possibly by reducing capillarypermeability. Preclinical in-vivo experiments demonstratedanti-inflammatory and capillary wall thickening effects.

DETAILED DESCRIPTION OF THE INVENTION

[0010] In a preferred embodiment, the dietary supplement is in a formsuitable for oral administration, in particular in a solid dosage form,i.e. a capsule or tablet, that consists of 20 to 60% of aqueous red vineleaf extract with a high flavonoid content of 2-15%. Another preferreddosage form is that of drops containing 3 to 90% of extract. Furthersuitable administration forms may be coated tablets, syrups, or thelike.

[0011] With the foregoing in mind, it is a primary object of the presentinvention to provide a dietary supplement for preventing and alleviatingthe discomfort associated with mild-to-moderate chronic venousinsufficiency of the lower extremities.

[0012] It is a further object of the present invention to provide adietary supplement for preventing and/or alleviating the discomfortassociated with mild-to-moderate chronic venous insufficiency of thelower extremities comprising herbal ingredients, wherein the dietarysupplement is manufactured pursuant to a controlled process thatpreserves the herbal curing qualities of the ingredients.

[0013] It is still a further object of the present invention to providea dietary supplement which is effective in preventing and/or alleviatingthe discomfort associated with mild-to-moderate chronic venousinsufficiency of the lower extremities.

[0014] It is still a further object of the present invention to providea dietary supplement for preventing and/or alleviating the discomfortassociated with mild-to-moderate chronic venous insufficiency of thelower extremities comprising herbal ingredients and having minimal or noside effects and thus being safe for internal consumption.

[0015] A fundamental part of the present invention is the preparation ofa supplement for oral administration containing an aqueous extractprepared from dried red vine leaves. The latter is characterised by ahigh content of 2 to 20%, preferably 2 to 10% of biologically activeflavonoids.

[0016] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way.

[0017] The examples which follow are illustrative and, as recognized byone skilled in the art, particular conditions could be modified asneeded for individual compositions. Materials used in tests below areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

[0018] The basis of the supplement is the aqueous extract of red vineleaves (foliae vitis viniferae L.). The starting material for thepreparation of the extract are red vine leaves collected at a point oftime where the content in flavonoids has reached an optimum. This isusually the case around the harvesting time of the grapes. The leavesare carefully dried and crushed. For extraction the leaves are cut topieces of preferably 5 to 10 mm. To achieve a high content in flavonoidsthe extraction is done at elevated temperature, preferably at atemperature in the range of 60° to 80° C., over a time of at least 6 upto 10 hours. The preferred method is that of an exhaustive percolation.

[0019] The so-called fluid extract obtained in the course of theextraction may be directly used in the preparation of liquid dosageforms. In order to get a more concentrated extract preferably at leastpart of the solvent is removed by use of a suitable evaporator. Thethick extract obtained in this step may again be directly used in themanufacturing of liquid dosage forms.

[0020] For the preparation of solid dosage forms the thick extract isdried, for instance by use of a vacuum drying oven or a vacuum dryingconveyer. Carriers or excipients may be added during drying tofacilitate further processing of the extract. Such carriers orexcipients may be silicon dioxide, maltodextrine, glucose syrup,cellulose and others.

[0021] The supplement for oral administration is manufactured usingusual techniques applied in the food industry or in the pharmaceuticalindustry. Preferred administration forms are tablets, including coatedtablets or capsules. But also liquid preparations, preferably drops, maybe chosen.

[0022] To prevent and/or alleviate the discomfort of mild-to-moderatechronic venous insufficiency of the lower extremities, the dietarysupplement should be taken in dosages corresponding to 80-1000 mg ofextract, preferably 300-800 mg, in particular 350-750 mg daily. Thetotal amount of extract may be divided up in 1 to 3 capsules or tabletsa day (or an equivalent dose by means of a liquid form). The daily doseshould be taken at once, preferably in the morning.

[0023] Impressive improvement of the symptoms can be expected within 6weeks of continuous use. The optimum effect is maintained or amplifiedon longer use.

[0024] In order to verify the effectiveness, safety and tolerability ofthe dietary supplement of the present invention, a randomised,placebo-controlled, double-blind parallel-group study was conducted in alarge and representative sample of patients with evidence ofmild-to-moderate chronic venous insufficiency of the lower extremities.This study was carried out in accordance with the Declaration ofHelsinki and the Principles of Good Clinical Practice. The results areset forth below:

[0025] Objective—To assess the efficacy and safety of once-daily dosesof 360 and 720 mg red vine leaf extract (RVLE) compared to placebo inpatients with grade I and incipient grade II chronic venousinsufficiency (CVI).

[0026] Design—A 12-week, randomised, double-blind, placebo-controlled,parallel-group, multi-center study.

[0027] Patients—Male and female outpatients between 25 and 75 years ofage with grade I and grade II CVI (i.e. without extensive trophicchanges), without further significant medical conditions and not treatedwith compression stockings, diuretics or other drugs affecting fluidbalance.

[0028] Intervention—Patients were randomly assigned to a double-blindtreatment with placebo, 360 mg RVLE or 720 mg RVLE once daily for 12weeks, preceded and followed by a single-blind 2-week placebo treatmentfor baseline run-in and end-of-trial washout, respectively. Studycriteria were evaluated at baseline, after 6 and 12 weeks of treatmentand 2 weeks after discontinuation of treatment.

[0029] Outcome Measures—Primary outcome measure: Change in lower legvolume, as determined by water displacement plethysmography. Secondaryoutcome measures: Change in ankle and calf circumference; change inintensity of key symptoms (“tired, heavy legs”, “feeling of tenseness”,“tingling sensation”, and “tenderness/pain”) compared to baseline.

[0030] Results—Of the 260 patients enrolled and randomised, 219completed the study in accordance with the protocol. In theintention-to-treat analysis (N=257), the mean (±SD) lower leg volume ofthe patients treated with placebo (N=87) increased by 15.2±90.1 g(displaced water mass) compared to baseline after 6 weeks of treatmentand by 33.7±96.1 g compared to baseline after 12 weeks of treatment. Inpatients treated with RVLE according to this invention, however, lowerleg volume decreased and, after 12 weeks of treatment, the difference inmean lower leg volume between the active treatment groups and theplacebo group was −75.9 g (95% CI: −106.1 to 45.8 g) for the 360-mg RVLEgroup (N=86) and −99.9 g (95% CI: −130.3 to −69.6 g) for the 720-mg RVLEgroup (N=84). The changes in calf circumference showed a similarpattern; in patients treated with RVLE, both the higher dose (720 mg)and, to a lesser extent, the lower dose (360 mg) resulted in a clearreduction in circumference over time, whereas, in patients treated withthe placebo, the circumferences remained largely unchanged (95% CI ofthe estimated treatment effects vs. placebo after 12 weeks: −1.40 to−0.56 cm for 360 mg RVLE and −1.73 to −0.88 cm for 720 mg RVLE). Thereductions in ankle circumference were qualitatively similar butquantitatively less marked.

[0031] There was a clear improvement in key CVI symptoms at 6 weeks withall treatments, but a further improvement at week 12 was seen only inthe active treatment groups; at 12 weeks, the changes compared tobaseline were significantly greater (p<0.001) in both active treatmentgroups than in the placebo group. The treatments were well tolerated.Adverse events were rare and usually mild. Two AEs during treatment withthe placebo led to hospitalisation. Three further patients werewithdrawn because of AEs which occurred during treatment with theplacebo.

[0032] Conclusion—Once-daily doses of 360 and 720 mg RVLE appeared safeand effective in the treatment of mild CVI, reducing lower leg oedemaand circumference whilst improving key CVI-related symptoms. The extentof oedema reduction is at least equivalent to that reported forcompression stockings and/or other oedema-reducing agents. The higherdose was as well tolerated as the lower dose but resulted in a slightlygreater and more sustained improvement.

[0033] It will be readily apparent to those skilled in the art thatvarious changes and modifications of an obvious nature may be madewithout departing from the spirit of the invention, and all such changesand modifications of an obvious nature may be made without departingfrom the spirit of the invention, and all such changes and modificationsare considered to fall within the scope of the invention, as defined bythe claims as defined. While the composition of the present inventionhas been set forth in what is believed to be preferred embodiments, itis recognised that departures may be made within the spirit and scope ofthe following claims which, therefore, should not be limited exceptwithin the doctrine of equivalents.

What is claimed is:
 1. An improved composition in a form suitable fororal administration consisting of an active principle, and apharmaceutically, cosmetically or dietetically acceptable carrier, theimprovement wherein is that said active principle consists essentiallyof an aqueous extract of red vine leaves containing: 2 to 20% flavonoidsand less than about 0.15% anthocyanins; wherein said aqueous extract ofred vine leaves is obtainable by a method comprising the steps of: (a)collecting red vine leaves at a point of time when the content inflavonoids has reached an optimum; (b) drying and crushing the leaves;(c) cutting the leaves to pieces; (d) extracting the leaves with waterat temperatures from 60 to 80° C. for 6 to 10 hours in an exhaustivepercolation; and, optionally, (e) concentrating the obtained extract;and wherein the improved composition contains an amount of said aqueousextract of red vine leaves sufficient for administration in dosagescorresponding to 350-750 mg daily.
 2. The composition according to claim1, which consists of 20 to 60% of the active principle.
 3. Thecomposition according to claim 1, wherein the aqueous extract of redvine leaves contains 2 to 10% flavonoids.
 4. The composition accordingto claim 1, wherein the flavonoids are present within the range of 1% to10% relative to the total mass of the composition.
 5. The compositionaccording to claim 1, which contains quercetin-3-O-β-D-glucuronide andisoquercitrin (quercetin-3-O-β-glucofuranoside).
 6. The compositionaccording to claim 1, which contains more than about 18.0% polyphenols.7. The composition according to claim 1, which is in the form ofgranules, tablets, capsules, drops or syrups.
 8. The compositionaccording to claim 1, wherein the total amount of extract is divided upin 1 to 3 capsules or tablets a day.